Aminochlorination reaction with N-chlorophthalimide as a new nitrogen/chlorine source resulting in α-amino derivatives

Article abstract of DOI:10.1016/j.tet.2012.05.066

A commercial available compound, N-chlorophthalimide was reported as an efficient nitrogen/chlorine source for the aminohalogenation of β-nitrostyrenes, which tolerates a wide range of β-nitrostyrenes substrates with good chemical yields, as well as excellent regioselectivities. The resulted vicinal haloamino nitro products have been converted into several other valuable α-amino compounds under simple and mild conditions.

Full text of DOI:10.1016/j.tet.2012.05.066

Tetrahedron 68 (2012) 6198e6203
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Aminochlorination reaction with N-chlorophthalimide as a new nitrogen/chlorine
source resulting in
a
-amino derivatives
,
b
a,
*
Yu Qian a, Xiaoyun Ji a, Wei Zhou a, Jianlin Han a , Guigen Li , Yi Pan
*
a School of Chemistry and Chemical Engineering, Nanjing University, State Key Laboratory of Coordination, Nanjing 210093, China
b Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A commercial available compound, N-chlorophthalimide was reported as an efficient nitrogen/chlorine
Received 31 March 2012
Received in revised form 12 May 2012
Accepted 18 May 2012
source for the aminohalogenation of
b-nitrostyrenes, which tolerates a wide range of b-nitrostyrenes
substrates with good chemical yields, as well as excellent regioselectivities. The resulted vicinal hal-
oamino nitro products have been converted into several other valuable
simple and mild conditions.
a-amino compounds under
Available online 26 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N-Chlorophthalimide
Aminohalogenation
b-Nitrostyrenes
a
-Amino compounds
1. Introduction
reported some nitrogen sources for the aminohalogenation of these
electron-deficient alkenes, such as N,N-dichlorosulfonamide, suc-
cinimide/NCS, N-bromoacetamide, benzamides/NCS,12,13 tert-butyl
N,N-dichlorocarbamate,15 benzyl carbamate/NCS,16 N,N-dibro-
mourethane17 and so on. However, the aminohalogenation of
Aminohalogenation and related reactions of functionalized
olefins have been reported as one of the most useful tools for the
synthesis of vicinal haloamines,1,2 by constructing carbon-nitrogen
and carbon-halogen bonds in tandem way at the same time.3e7 The
pioneer works about aminohalogenation reaction were found in
the 1960s, with simple alkenes as substrates. These reactions have
many of the characteristics of a free-radical addition reaction,
which resulted in moderate yields and low stereoselectivities.8 In
the past several years, a lot of highly regio- and stereoselective
systems have been developed for aminohalogenation of func-
b-nitrostyrenes proceeding through chloronium intermediates or
Michael adducts, still remained unclear, which seemed to depend
on the nitrogen sources.12e17 So, exploration of more nitrogen
sources for the aminohalogenation of
great need. In our continuous work on this reaction, we found that
N-chlorophthalimide could reaction with -nitrostyrenes under
simple conditions. Herein, we would like to report an efficient
aminochlorination of -nitrostyrenes with N-chlorophthalimide as
b-nitrostyrenes becomes in
b
tionalized alkenes, which included
a
,
b
b
-unsaturated carboxylic
b
esters,9 -unsaturated nitriles,10
a
,
b
a
,
-unsaturated ketones.11
a new nitrogen source promoted by NaOH (Scheme 1). N-Chlor-
ophthalimide was a commercial available compound and with
higher thermal stability comparing with the previous reported ni-
trogen sources, which made the reaction was very facile and
practical.
However, the nitrogen sources for these aminohalogenation re-
actions were still not well documented until now, and only sul-
fonamides were efficient for these reaction.9e11 So, the
development of aminohalogenation still remains very difficult and
great challenging.
Recently, b-nitrostyrenes, representing a new type of substrates,
2. Results and discussion
were reported for the aminohalogenation and attracted many re-
search interests, due to their higher reactivity.12,13 Furthermore, the
resulting haloamino nitro products can be easily converted into
corresponding vicinal diamines.14 We and other groups have
Initially, b-nitrostyrene 2a was chosen as the substrate for op-
timizing the aminohalogenation conditions (Table 1). The reaction
was carried out under previous catalytic conditions12b with
dichloromethane as solvent and Ni(OAc)2 as catalyst at room
temperature (entry 1, Table 1). No desired haloamide product was
observed at all and most of the starting materials remained after
48 h. Then, several other metal catalysts were tried for the reaction,
* Corresponding authors. Tel.: þ86 25 83592846; fax: þ86 25 83593153; e-mail
addresses: hanjl@nju.edu.cn (J. Han), yipan@nju.edu.cn (Y. Pan).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.066

Y. Qian et al. / Tetrahedron 68 (2012) 6198e6203
6199
Ar
NO2
O
O
Cl
NaOH
N Cl
NO2
N
Cl
Ar
CH2Cl2, rt
O
O
2
1
3
Scheme 1. N-Chlorophthalimide as nitrogen source for aminohalogenation reaction.
but giving no obvious improvement on the chemical yields at all
(entries 2e11). Fortunately, the desired product was observed with
29% yield in the presence of 20 mol % NaOH (entry 12). Encouraged
by this result, the further optimization was carried out by in-
creasing the amount of N-chlorophtahlimide, and a slightly higher
chemical yield was obtained (35%, entry 13). After careful studies,
we found the chemical yield could be increased to 92% when
3 equiv of NaOH was used (entry 17).
Table 2
Aminohalogenation of
b
-nitrostyrene with various solventsa
O
NO2
NO2
O
Cl
NaOH (3 equiv)
N
Cl
N
Cl
O
O
1
2a
3a
Table 1
Aminohalogenation of
b
-nitrostyrene with various catalystsa
Entry
Solvent
Time (h)
Temperature
Yields (%)b
1
2
3
4
5
6
7
8
CH3CN
PhMe
DMF
DMSO
THF
MeOH
Acetone
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
48
48
48
48
48
48
48
48
8
12
24
36
72
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
55
91
25
NRc
47
NRc
26
92
35
40
61
68
93
O
NO2
NO2
cat
O
Cl
N
Cl
N
Cl
CH2Cl2, rt
O
O
1
2a
3a
9
10
11
12
13
Entry
Catalyst (mol %)
Ratio (2a:1)
Yields (%)b
1
2
3
4
5
6
7
8
Ni(OAc)2 (20%)
K2CO3 (20%)
K2CO3/Ni(OAc)2 (20%)
MgSO4 (20%)
Mn(OAc)2 (20%)
KOH (20%)
K3PO4 (20%)
NaOAc (20%)
DMAP (20%)
Triethylamine (20%)
(CH3)3CONa (20%)
NaOH (20%)
NaOH (20%)
NaOH (50%)
NaOH (150%)
NaOH (200%)
NaOH (300%)
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:3
1:3
1:3
1:3
1:3
NRc
13%
13%
NRc
NRc
15%
13%
NRc
NRc
NRc
25%
29%
35%
44%
58%
69%
92%
a
Conditions:
b-nitrostyrene 2a (0.5 mmol), N-chlorophtahlimide (1.5 mmol),
3 equiv NaOH, in solvent (3 mL) at room temperature under N2.
b
Isolated yields.
No reaction was observed.
c
9
After obtaining the optimized reaction conditions, we then ex-
amined the scope of the aminohalogenation reaction by using
a variety of b-nitrostyrenes (Table 3). The transformation with N-
10
11
12
13
14
15
16
17
chlorophtahlimide as nitrogen/chlorine source can proceed
smoothly for a wide range of substrates, giving moderate to ex-
cellent chemical yields. The substituent groups on the aromatic ring
showed effect on the reaction. Generally, the reaction of electron-
rich substrates gave moderate chemical yields, and for the case of
methoxyl substituent, only 66% yield was found (entry 10). The
electron-deficient substrates were more suitable for the current
reaction, resulting in good to excellent chemical yields, even
though the substituent groups were fluoro (entries 6 and 7), tri-
fluoromethyl (entry 15). We then examined the substrates with
double substituted aromatic ring (2k and 2l), and the results
showed that they could also work well, giving the desired products
a
Conditions:
b-nitrostyrene 2a (0.5 mmol), N-chlorophtahlimide, in CH2Cl2
(3 mL) at room temperature under N2.
b
Isolated yields.
No reaction was observed.
c
Then, the scan of various organic solvents was carried out in the
presence of NaOH to improve the reaction efficiency (Table 2).
Solvent was found to play an important role in the current system.
No aminohalogenation product was observed at all when DMSO or
methanol was used as solvent (entries 4 and 6). The reaction with
acetonitrile, THF, DMF or acetone as solvent could also give the
desired haloamine products, along with moderate yields (entries 1,
3, 5 and 7). Notably, toluene was also a good choice for the current
system, resulting in a good chemical yield (91%, entry 2). The best
solvent for the reaction was dichloromethane, giving the desired
product with the highest yield (entry 8). After careful studies, we
found that 48 h was needed for the reaction to consume all
the starting material. Shortening the reaction time resulted in
dramatically lower yields (entries 9e12).
(entries 11 and 12). Notably, 1-naphthyl and 2-naphthyl b-nitro-
styrene (2m and 2n) was well tolerated in the reaction along with
good chemical yields (entries 13 and 14). Surprisingly, the reaction
of the substrates with ortho-substituted aromatic ring (2d) gave an
obvious lower yield (entry 4) than those of the substituents on
other positions. It was mainly because that the steric hindrance of
the substrate inhibited the addition of nitrogen/chlorine source.
Furthermore, excellent regioselectivities were detected for all the
cases, and only one regio isomer was obtained from the reaction.
The structure of these obtained dichlorinated haloamides has been
unambiguously confirmed by the X-ray diffraction analysis of
3d (Fig. 1).

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Y. Qian et al. / Tetrahedron 68 (2012) 6198e6203
Table 3
According to the previous studies on the aminohalogenation
b
-nitrostyrene12ꢀ17 and the resulted regioselectivity from the
The scope of the aminohalogenationa
of
Ar
NO2
current aminohalogenation system, a mechanism involving the
formation of chloronium intermediate was presented in Scheme 2
for this aminohalogenation reaction with N-chlorophtahlimide as
nitrogen/chlorine source. In the initial step, N-chlorophtahlimide
is activated by NaOH,18 forming the intermediates A1 and A2. Then,
O
O
Cl
NaOH (3 equiv)
CH2Cl2, rt
N
Cl
NO2
N
Cl
Ar
O
O
2
1
3
A1 adds to
termediate B. The chloronium intermediate B undergoes ring-
opening process, attacked by A2 on its -position, which is more
positively charged than its -position with the aid of NaOH,
resulting in intermediate C, a normal monohaloamino product. The
final step is the formation of dichlorinated compound 3a via
deprotonation/electrophilic chlorination of precursor C.
The presence of chloro and nitro functionalities in the resulted
vicinal chloroamino nitro products provided an easy access to vari-
ous other valuable organic blocks by intermolecular or intra-
molecular reactions. When the product 3a was stirred in methanol
in the presence of Pd/C under the hydrogen atmosphere at
room temperature for 16 h, two new compounds were isolated
b-nitrostyrene 2a, generating the chloronium in-
Entry
Substrate
Ar
C6H5
2-ClC6H4
4-MeC6H4
2-OBnC6H4
4-ClC6H4
4-FC6H4
Product
Yields (%)b
a
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
92%
93%
76%
35%
94%
90%
74%
75%
80%
66%
87%
67%
80%
71%
72%
b
3-FC6H4
4-BrC6H4
3-BrC6H4
4-OMeC6H4
3-Br-4-OMeC6H3
3-Cl-4-ClC6H3
1-Naphthyl
9
10
11
12
13
14
15
(Scheme 3). One was
-amino nitro compounds 5 with 56% yield.
More importantly, when the reaction time was prolonged to
48 h, the nitro group in 5 could undergo the other reduction
a-amino acetal 4 with 31% yield, the other was
2-Naphthyl
4-CF3C6H4
a
a
Conditions:
b-nitrostyrenes 2 (0.5 mmol), N-chlorophtahlimide (1.5 mmol),
3 equiv NaOH, in CH2Cl2 (3 mL) at room temperature under N2.
b
Isolated yields.
Fig. 1. ORTEP diagram drawing of 3d (CCDC number: 824479).
O
N H
O
NaOH
NO2
O
NaOCl
A1
A2
Ph
O
Cl NO2
2a
N Cl
Ph
B
1
O
O
Ph
N
NO2
Cl
Ph
N
NO2
Cl
Cl
N H
N Cl
O
O
O
O
A2
O
O
NaOH
C
3a
Scheme 2. Proposed mechanism for the reaction.

Y. Qian et al. / Tetrahedron 68 (2012) 6198e6203
6201
Pd/C, H2, rt
O
O
O
O
N
N
O
O
N
CH3OH, 16 h
OMe
OMe
NO2
H
NO2
Cl
H
H
Cl
5
4
3a
56% yield
31% yield
Scheme 3. Conversion of 3a catalyzed by Pd/C for 16 h.
process. Almost all of 5 was converted into vicinal diamine 6 with
48% chemical yield (Scheme 4), and 4 was remained.
temperature with good to excellent yields and high regiose-
lectivities. The resulted chloroamino nitro compounds have
Finally, the product 3a was subjected to DABCO/CH2Cl2 system
been converted into
a
-amino acetal,
a-amino nitro compounds,
at room temperature for 10 min,
a
,b
-unsaturated vicinal haloamino
vicinal diamine,
a,b-unsaturated vicinal haloamino nitro com-
nitro compound 7 was obtained in 63% yield. 3a was also easily to
be esterified by treatment with sodium methoxide for 1 h, resulting
in compound 8 with the yield of 85% (Scheme 5).
pound and so on. Further study on asymmetric amino-
halogenation of this new type of nitrogen source is presently
under progress.
Pd/C, H2, rt
O
O
O
O
O
O
N
N
N
CH3OH, 48 h
NH2
H
NO2
Cl
OMe
OMe
H
Cl
H
4
6
3a
Scheme 4. Conversion of 3a catalyzed by Pd/C for 48 h.
O
CH3ONa, rt
CH2Cl2, 1 h
MeO
DABCO, rt
CH2Cl2, 10 min
O
O
HN
O
NO2
Cl
N
O
O
N
NO2
Cl
NO2
Cl
8 85% yield
Cl
Cl
7 63% yield
3a
Scheme 5. Derivatization reaction of 3a.
3. Conclusion
In summary, a regioselective aminochlorination of
4. Experimental section
4.1. General
b
-nitro-
styrenes with N-chlorophtahlimide as a new nitrogen/chlorine
source under mild conditions has been developed. The system
was convenient to carry out in the presence of NaOH at room
Reaction progress was monitored by TLC using silica gel 60F-254
with detection by UV. Flash chromatography was performed using

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Y. Qian et al. / Tetrahedron 68 (2012) 6198e6203
silica gel 60 (200e300mesh) with freshly distilled solvents. Melting
points are uncorrected. 1H and 13C NMR (TMS used as internal
standard) spectra were recorded with a Bruker ARX300 spec-
trometer. High resolution mass spectra for all the new compounds
were done by Micro mass Q-Tof instrument (ESI). The crystal
structure was recorded on a X-ray diffraction spectrometer.
117.05, 114.21, 63.80. HRMS (ESI/[MþNa]þ) Calcd. For:
C16H9Cl2FN2O4Na 404.9821, found 404.9836.
4.2.8. 3h. White solid. Mp 134e136 ꢁC. 1H NMR (300 MHz, CDCl3):
d
7.85e7.95 (m, 2H), 7.75e7.84 (m, 2H), 7.67 (d, J¼8.7 Hz, 2H), 7.50
(d, J¼8.4 Hz, 2H), 6.61 (s, 1H). 13C NMR (75 MHz, CDCl3)
d 166.60,
134.93, 132.44, 131.96, 131.00, 129.89, 124.64, 124.14, 114.21, 63.89.
HRMS (ESI/[MþNa]þ) Calcd. For: C16H9BrCl2N2O4Na 464.9020,
found 464.9003.
4.2. General procedure for aminohalogenation
Into a dry reaction tube were added the 2 (0.5 mmol), N-
chlorophtahlimide (1.5 mmol), NaOH (1.5 mmol), and they were
mixed with freshly distilled CH2Cl2 (3.0 mL) under nitrogen at-
mosphere. The mixture was stirred at room temperature for 48 h.
The reaction was then quenched by saturated aqueous Na2SO3
(2.0 mL) solution. The solid precipitates were filtered off and the
filtrate was extracted with CH2Cl2 three times. Then the combined
organic phase was washed with brine and dried with anhydrous
Na2SO4. After being concentrated, the mixture was purified via
column chromatography with ethyl acetate and petroleum ether
(v/v¼1:4) as eluent to give the product.
4.2.9. 3i. White solid. Mp 100e103 ꢁC. 1H NMR (300 MHz, CDCl3):
d
7.85e8.00 (m, 3H), 7.74e7.84 (m, 3H), 7.48e7.60 (m, 1H),
7.22e7.32 (m, 1H), 6.60 (s, 1H). 13C NMR (75 MHz, CDCl3)
d
166.55,
134.98, 133.69, 133.23, 132.95, 130.97, 130.20, 129.37, 124.18, 122.61,
114.13, 63.72. HRMS (ESI/[MþNa]þ) Calcd. For: C16H9BrCl2N2O4Na
464.9020, found 464.9031.
4.2.10. 3j. White solid. Mp 130e132 ꢁC. 1H NMR (300 MHz, CDCl3):
d
7.85e7.95 (m, 2H), 7.71e7.81 (m, 4H), 6.87 (d, J¼8.7 Hz, 2H), 6.61 (s,
1H), 3.80 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
166.79, 160.71, 134.77,
132.47,131.14,124.00,122.67,114.93,113.98, 64.25, 55.30. HRMS (ESI/
4.2.1. 3a. White solid. Mp 124e126 ꢁC. 1H NMR (300 MHz, CDCl3):
[MþNa]þ) Calcd. For: C17H12Cl2N2O5Na 417.0021, found 417.0015.
d
7.85e7.95 (m, 2H), 7.70e7.84 (m, 4H), 7.32e7.45 (m, 3H), 6.67 (s,
1H). 13C NMR (75 MHz, CDCl3)
d
166.68, 134.82, 131.09, 131.01,
4.2.11. 3k. White solid. Mp 112e114 ꢁC. 1H NMR (300 MHz, CDCl3):
130.73, 130.03, 128.74, 124.05, 114.66, 64.52. HRMS (ESI/[MþNa]þ)
d
7.97 (d, J¼2.1 Hz, 1H), 7.86e7.94 (m, 2H), 7.75e7.84 (m, 3H),
Calcd. For: C16H10Cl2N2O4Na 386.9915, found 386.9910.
6.86e6.92 (d, J¼8.7 Hz, 1H), 6.55 (s, 1H), 3.90 (s, 3H). 13C NMR
(75 MHz, CDCl3)
d 166.66, 157.10, 135.86, 134.91, 131.49, 131.01,
4.2.2. 3b. White solid. Mp 131e132 ꢁC. 1H NMR (300 MHz, CDCl3):
124.11, 123.94, 114.52, 111.62, 111.44, 63.53, 56.32. HRMS (ESI/
d
8.32e8.42(m,1H), 7.73e7.91 (m, 4H), 7.30e7.44 (m, 3H), 7.03 (s,1H).
[MþNa]þ) Calcd. For: C17H11BrCl2N2O5Na 494.9126, found 494.9137.
13C NMR (75 MHz, CDCl3)
d
166.27, 134.86, 134.68, 131.64, 130.99,
130.95, 130.11, 128.58, 126.50, 124.04, 114.39, 59.98. HRMS (ESI/
4.2.12. 3l. White solid. Mp 129e131 ꢁC. 1H NMR (300 MHz, CDCl3):
[MþNa]þ) Calcd. For: C16H9Cl3N2O4Na 420.9526, found 420.9520.
d
7.87e7.98 (m, 3H), 7.75e7.85 (m, 2H), 7.60e7.71 (m, 1H),
7.37e7.50 (m, 1H), 6.58 (s, 1H). 13C NMR (75 MHz, CDCl3)
d
166.50,
4.2.3. 3c. White solid. Mp 116e117 ꢁC. 1H NMR (300 MHz, CDCl3):
135.04, 134.84, 132.79, 130.91, 130.81, 130.63, 130.07, 128.33, 124.24,
113.90, 63.29. HRMS (ESI/[MþNa]þ) Calcd. For: C16H8Cl4N2O4Na
456.9106, found 456.9103.
d
8.84e8.95 (m, 2H), 7.72e7.83 (m, 2H), 7.65e7.72 (m, 2H),
7.15e7.23 (m, 2H), 6.63 (s, 1H), 2.34 (s, 3H). 13C NMR (75 MHz,
CDCl3) d 166.74, 140.19, 134.78, 131.14, 130.68, 129.42, 127.91, 124.01,
114.75, 64.37, 21.24. HRMS (ESI/[MþNa]þ) Calcd. For:
4.2.13. 3m. White solid. Mp 186e188 ꢁC. 1H NMR (300 MHz, CDCl3):
C17H12Cl2N2O4Na 401.0072, found 401.0066.
d
8.55e8.65 (m, 1H), 8.00 (d, J¼8.4 Hz, 1H), 7.80e7.96 (m, 4H),
7.70e7.78 (m, 2H), 7.45e7.61 (m, 4H). 13C NMR (75 MHz, CDCl3)
166.72,134.77, 133.90, 131.39,130.99,130.79,129.58,128.90,127.84,
4.2.4. 3d. White solid. Mp 131e133 ꢁC. 1H NMR (300 MHz, CDCl3):
d
d
8.15e8.23 (m,1H), 7.69e7.83 (m, 4H), 7.21e7.38 (m, 6H), 7.15 (s,
126.03, 125.75, 124.61, 124.02, 121.61, 115.01, 58.76. HRMS (ESI/
1H), 7.00e7.08 (m,1H), 6.91 (d, J¼8.4 Hz,1H), 4.97e5.10 (m, 2H). 13C
[MþNa]þ) Calcd. For: C20H12Cl2N2O4Na 437.0072, found 437.0066.
NMR (75 MHz, CDCl3)
d 166.59, 156.06, 135.90, 134.44, 131.23,
130.82, 130.64, 128.53, 128.06, 127.50, 123.83, 120.43, 119.64, 114.81,
112.19, 70.57, 57.14. HRMS (ESI/[MþNa]þ) Calcd. For:
C23H16Cl2N2O5Na 493.0334, found 493.0328.
4.2.14. 3n. White solid. Mp 171e173 ꢁC. 1H NMR (300 MHz, CDCl3):
d
8.24 (s, 1H), 7.73e7.97 (m, 8H), 7.48e7.58 (m, 2H), 6.99 (s, 1H). 13
C
NMR (75 MHz, CDCl3) d 166.78, 134.82, 133.60, 132.77, 131.11, 131.03,
128.60, 128.49, 128.37, 127.62, 127.47, 127.16, 126.73, 124.07, 114.67,
64.66. HRMS (ESI/[MþNa]þ) Calcd. For: C20H12Cl2N2O4Na 437.0072,
found 437.0081.
4.2.5. 3e. White solid. Mp 112e115 ꢁC. 1H NMR (300 MHz, CDCl3):
d
7.85e7.95 (m, 2H), 7.70e7.85 (m, 4H), 7.30e7.40 (m, 2H), 6.62 (s,
1H). 13C NMR (75 MHz, CDCl3)
d 166.62, 136.30, 134.93, 132.23,
131.01, 129.36, 128.98, 124.14, 114.30, 63.83. HRMS (ESI/[MþNa]þ)
4.2.15. 3o. White solid. Mp 41e43 ꢁC. 1H NMR (300 MHz, CDCl3):
Calcd. For: C16H14Cl2N2O4Na 420.9526, found 420.9532.
d
7.87e7.98 (m, 4H), 7.75e7.85 (m, 2H), 7.62e7.70 (m, 2H), 6.70 (s,
1H).13C NMR (75 MHz, CDCl3)
d
166.54,135.00,134.80,131.19,130.95,
4.2.6. 3f. White solid. Mp 133e135 ꢁC. 1H NMR (300 MHz, CDCl3):
129.42, 125.69, 125.64, 124.19, 113.97, 63.81, 29.71. HRMS (ESI/
d
7.87e7.95 (m, 2H), 7.75e7.85 (m, 4H), 7.00e7.12 (m, 2H), 6.64 (s,
[MþNa]þ) Calcd. For: C17H9Cl2F3N2O4Na 454.9789, found 454.9780.
1H). 13C NMR (75 MHz, CDCl3)
d
166.68, 165.13, 161.82, 134.89,
133.14, 133.02, 131.03, 126.78, 124.10, 115.93,115.64, 114.53, 63.86.
HRMS (ESI/[MþNa]þ) Calcd. For: C16H9Cl2FN2O4Na 404.9821, found
404.9823.
4.3. General procedure for reduction reaction of 3a catalyzed
by Pd/C
Into a dry reaction vial were added 3a (0.5 mmol), 10% Pd/C
(10 mg) and CH3OH (25 mL). The mixture was stirred at room
temperature under hydrogen for the desired reaction time then
passed through Celite. The Celite was washed with ether and the
organic phase was combined. After evaporation, the crude product
was purified by TLC plate.
4.2.7. 3g. White solid. Mp 97e98 ꢁC. 1H NMR (300 MHz, CDCl3):
d
7.85e7.95 (m, 2H), 7.73e7.85 (m, 2H), 7.60e7.70 (m, 1H),
7.45e7.52 (m,1H), 7.30e7.42 (m,1H), 7.05e7.15 (m,1H), 6.65 (s,1H).
13C NMR (75 MHz, CDCl3)
166.57, 164.02, 160.75, 134.94, 133.01,
130.99, 130.32, 130.21, 126.56, 126.52, 124.16, 118.11, 117.79, 117.32,
d

Y. Qian et al. / Tetrahedron 68 (2012) 6198e6203
6203
4.3.1. 4. White solid. Mp 123e124 ꢁC. 1H NMR (300 MHz, CDCl3):
7.76e7.85 (m, 2H), 7.66e7.73 (m, 2H), 7.55e7.63 (m, 2H),
7.23e7.38 (m, 3H), 5.73 (d, J¼9.3 Hz, 1H), 5.36 (d, J¼8.7 Hz, 1H), 3.37
(s, 3H), 3.33 (s, 3H). 13C NMR (75 MHz, CDCl3)
168.16, 136.89,
Fundamental Research Funds for the Central Universities (No.
1107020522 and No. 1082020502). The Jiangsu 333 program (for
Y.P.) and Changzhou Jin-Feng-Huang program (for J.H.) are also
acknowledged.
d
d
133.99, 131.89, 128.98, 128.63, 128.16, 123.34, 101.51, 56.04, 54.73,
53.26. HRMS (ESI/[MþNa]þ) Calcd. For: C18H17NO4Na 334.1050,
found 334.1048.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2012.05.066.
4.3.2. 5. White solid. Mp 129e130 ꢁC. 1H NMR (300 MHz, CDCl3):
d
7.79e7.90 (m, 2H), 7.67e7.78 (m, 2H), 7.47e7.60 (m, 2H),
7.31e7.43 (m, 3H), 6.11e6.17 (m, 1H), 5.79e5.92 (m, 1H), 5.02e5.08
References and notes
(m, 1H). 13C NMR (75 MHz, CDCl3)
d 167.71, 134.97, 134.47, 131.49,
129.27, 129.23, 127.98, 123.71, 74.20, 52.24. HRMS (ESI/[MþNa]þ)
1. Qui, J.; Silverman, R. B. J. Med. Chem. 2000, 43, 706e720.
Calcd. For: C16H12N2O4Na 319.0689, found 319.0615.
2. (a) Chen, D.; Timmons, C.; Guo, L.; Xu, X.; Li, G. Synthesis 2004, 2749e2784; (b)
Chen, D.; Kim, S. H.; Hodges, B.; Li, G. ARKIVOC 2003, xii, 56e63; (c) Chen, D.;
Guo, L.; Liu, J.; Kirtane, S.; Cannon, J. F.; Li, G. Org. Lett. 2005, 7, 921e924; (d)
Mei, H. B.; Yan, L. J.; Han, J. L.; Li, G.; Pan, Y. Chem. Biol. Drug Des. 2010, 76,
392e396.
4.3.3. 6. White solid. Mp 217e219 ꢁC. 1H NMR (300 MHz, DMSO-
d6):
d 8.29 (b, 2H), 7.85e7.91 (m, 4H), 7.31e7.39 (m, 5H), 5.54e5.66
(m, 1H), 4.04e4.11 (m, 1H), 3.52e3.58 (m, 1H). 13C NMR (75 MHz,
3. Kemp, J. E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; vol. 3, pp 469e513.
DMSO-d6)
d 168.49, 137.05, 135.10, 132.08, 129.37, 128.80, 127.52,
4. (a) Yeung, Y. Y.; Gao, X.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 9644e9645; (b)
Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1991, 113, 5863e5864; (c)
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123.72, 52.26, 39.68. HRMS (ESI/[MþH]þ) Calcd. For: C16H15N2O2
267.1129, found 267.1128.
4.4. General procedure for conversion of 3a to 7
Into a dry reaction vial were added 3a (0.5 mmol), DACBO
(1.5 mmol) and CH2Cl2 (4 mL). The mixture was stirred at room
temperature for 10 min. The mixture was directly purified by TLC
plate.
4.4.1. 7. Yellow solid. Mp 116e118 ꢁC. 1H NMR (300 MHz, CDCl3):
d
7.88e7.97(m, 2H), 7.78e7.87 (m, 2H), 7.48e7.58 (m, 2H),
7.26e7.47 (m, 3H). 13C NMR (75 MHz, CDCl3)
d
164.86, 135.15,
132.05, 131.61, 131.29, 131.25, 129.10, 128.87, 124.52. HRMS (ESI/
[MþNa]þ) Calcd. For: C16H9ClN2O4Na 351.0143, found 351.0140.
10. Han, J. L.; Zhi, S. J.; Wang, L. Y.; Pan, Y.; Li, G. Eur. J. Org. Chem. 2007, 1332e1337.
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4.5. General procedure for conversion of 3a to 8
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4236e4239; (b) Chen, D.; Timmons, C.; Chao, S.; Li, G. Eur. J. Org. Chem. 2004,
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Into a dry reaction vial were added 3a (0.5 mmol), MeONa
(2.5 mmol in 2.5 mL methonal) and CH2Cl2 (2 mL). The mixture was
stirred at room temperature for 1 h. The mixture was directly pu-
rified by TLC plate, giving product 8.
12. (a) Zhi, S. J.; Han, J. L.; Lin, C.; An, G. H.; Pan, Y.; Li, G. Synthesis 2008, 1570e1574;
(b) Zhi, S. J.; Sun, H.; Lin, C.; Zhang, G. Q.; Li, G.; Pan, Y. Sci. China Chem. 2010, 53,
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4.5.1. 8. White solid. Mp 150e151 ꢁC. 1H NMR (300 MHz, CDCl3):
7.87 (d, J¼6.9 Hz, 1H), 7.44e7.58 (m, 8H), 7.11 (d, J¼9.9 Hz, 1H), 6.47
(d, J¼10.5, 1H), 3.51 (s, 3H). 13C NMR (75 MHz, CDCl3)
d 168.03,
166.92, 136.33, 132.71, 132.23, 130.47, 130.38, 129.88, 129.14, 129.04,
128.80,127.88,115.45, 62.11, 52.40. HRMS (ESI/[MþNa]þ) Calcd. For:
C17H14Cl2N2O5Na 419.0177, found 419.0167.
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Acknowledgements
We gratefully acknowledge the financial support from the Na-
tional Natural Science Foundation of China (No. 21102071) and the